Impact of Host NF-kB Signaling in Radiation Therapy

项目总结/摘要 不同细胞表面活性剂诱导的C→N NF-κB信号通路的研究 受体的研究极大地扩展了关于该转录因子家族在 调节免疫/炎症反应和肿瘤发生。相比之下，DNA的生理作用 损伤诱导的核-胞质（N→C）NF-κB信号转导仍然知之甚少。拟议 这项研究将通过阐明N→C NF-κB信号转导在维持NF-κB活性中令人惊讶的关键作用来填补这一知识空白。 体内放射治疗（RT）期间的抗肿瘤CD 8 T细胞应答。目前的建议利用基因 改良的小鼠模型，其在体内选择性地使N→C NF-κB信号传导失活。初步数据显示， 放射治疗可以以依赖于CD 8 T细胞的方式诱导同源肿瘤的持续消退。 我们还发现，一种特殊类型的记忆性CD 8 T细胞在肿瘤控制中被扩增， 模型最后，我们已经产生了一个令人鼓舞的数据与NF-κ B DNA结合抑制剂，以诱导持续的 放射治疗后肿瘤消退。基于这些观察，我们假设， 宿主N→C NF-κB信号通路通过产生肿瘤抗原特异性记忆促进放射治疗 CD 8 T细胞。我们将通过定义持续的肿瘤控制介导的细胞机制来验证这一假设。 通过抑制宿主N→C NF-κB信号通路（目的1），阐明放射治疗中NF-κB的分子机制， 在放射治疗中通过抑制宿主N→C NF-κB信号传导介导的持续肿瘤控制（Aim 2）和靶点 宿主N→C NF-κB信号传导与化学抑制剂，以改善放射治疗（目的3）。拟定研究 这是因为N→C NF-κB信号在调节宿主肿瘤反应中的生理作用是重要的， 完全不确定，这项研究将填补这一知识空白。它是创新的，因为一种新的小鼠模型， 将使用一种目前正在进行2期临床试验的新型化学抑制剂。最后，高影响是 这是因为上述抑制剂化学靶向N→C NF-κB信号传导可能会及时加速 转化为临床试验。

PROJECT SUMMARY / ABSTRACT Investigation of cytoplasmic-to-nuclear (C→N) NF-κB signaling pathways induced by various cell surface receptors has significantly expanded the knowledge regarding the role of this transcription factor family in regulating immune/inflammatory responses and tumorigenesis. By contrast, the physiological role of DNA damage-induced nuclear-to-cytoplasmic (N→C) NF-κB signaling remains poorly understood. The proposed study will fill this knowledge gap by elucidating a surprising and crucial role of N→C NF-κB signaling in sustaining anti-tumor CD8 T cell responses during radiotherapy (RT) in vivo. The current proposal utilizes a genetically modified mouse model that selectively disables N→C NF-κB signaling in vivo. Our preliminary data show that radiation therapy can induce sustained regression of syngeneic tumors in a manner dependent on CD8 T cells. We also found that a special type of memory CD8 T cells implicated in tumor control is expanded in this mouse model. Finally, we have generated an encouraging data with an NF-kB DNA binding inhibitor to induce sustained tumor regression following radiation therapy. Based on these observations, we hypothesize that inhibition of N→C NF-κB signaling in the host improve radiation therapy via generation of tumor antigen-specific memory CD8 T cells. We will test this hypothesis by define the cellular mechanism of sustained tumor control mediated by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 1), elucidate the molecular mechanism of sustained tumor control mediated by inhibiting host N→C NF-κB signaling in radiation therapy (Aim 2) and target host N→C NF-κB signaling with a chemical inhibitor to improve radiation therapy (Aim 3). The proposed study is significant because the physiological role of N→C NF-κB signaling in modulating host tumor response is completely undefined and this study will fill this knowledge gap. It is innovative because a new mouse model and a novel chemical inhibitor currently undergoing Phase 2 clinical trials will be employed. Finally, a high impact is expected because chemical targeting of N→C NF-κB signaling by the above inhibitor may expedite timely translation to clinical trials.